Herpes simplex virus alters Alzheimer's disease biomarkers - A hypothesis paper.

INTRODUCTION: Human herpes simplex virus 1 (HSV1) is discussed to induce amyloid-ß (Aß) accumulation and neurofibrillary tangles of hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) in cell culture and animal models. Aß appears to be virostatic. We investigated the association between intrathecal antibodies against HSV or cytomegalovirus (CMV) and cerebrospinal fluid (CSF) AD biomarkers. METHODS: Aß42 /Aß40 ratio, pTau, and tTau were measured in CSF of 117 patients with early AD positive for amyloid pathology (A+) and 30 healthy controls (A-). CSF-to-serum anti-HSV1/2-IgG antibody indices (AI-IgGHSV1/2 ) and CMV (AI-IgGCMV ) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Exclusively in HSV1-seropositive AD, pTau was positively and significantly predicted by AI-IgGHSV1/2 and negatively by the Aß42 /Aß40 ratio in both univariate and multivariate regression analyses. Furthermore, a significant and negative interaction between the AI-IgGHSV1/2 and Aß42 /Aß40 ratio on pTau was found. DISCUSSION: The results support the hypothesis that HSV infection contributes to AD. HIGHLIGHTS: HSV antibody index is positively associated with tau pathology in patients with AD. HSV antibody index is negatively associated with cerebral FDG metabolism. Amyloid modulates the association of HSV antibody index with CSF-pTau. HSV in AD offers a pathophysiological model connecting tau and amyloid.

[Mild cognitive impairment in geriatric practice: patient orientation, diagnostics, treatment and ethics]. / Leichte kognitive Beeinträchtigung (MCI) in der altersmedizinischen Praxis: Patientenorientierung, Diagnostik, Behandlung und Ethik.

Mild cognitive impairment (MCI) is a common problem in old people, which can be distressing for patients and their families. The main feature of MCI is a decrease in cognitive performance with activities of daily living still unimpaired. The identification of treatable risk factors, recognition of early cognitive changes and a timely differential diagnosis, comprehensive information and counselling are important tasks in geriatric medicine. The aim of this article is to present practical recommendations to support physicians working with geriatric patients in recognizing cognitive deficits at an early stage, provide high-quality care focusing on counselling, treatment, and comorbidity management and to maximize the potential of the available treatment options.

[Mathilde Ludendorff (1877-1966): specialist for nervous and mental diseases and Germanic philosopher]. / Mathilde Ludendorff (1877­1966): Nervenärztin und völkische Philosophin.

Mathilde Ludendorff (nee Spiess, widowed von Kemnitz, divorced Kleine) was one of the first women who studied medicine in Imperial Germany. She wrote a feminist doctoral thesis, refuted Sigmund Freud's psychoanalysis early in her career, detected the fraud of Albert von Schrenck-Notzing's spiritualist research, became a specialist for nervous and mental diseases after only 17 months of training with Emil Kraepelin, as his-according to her own words-best pupil, treated General Ludendorff's first wife and soon became his second, developed a Germanic philosophy too radical for Adolf Hitler's taste, was considered as a primary culprit after a first denazification trial in 1949 and contested the expert opinion of her colleague Professor Georg Stertz about her own mental state. Her books are still in print and her Alliance for God Cognizance (Ludendorff) still exists and is monitored by the National Intelligence Agency.

18F-FIBT may expand PET for ß-amyloid imaging in neurodegenerative diseases.

18F-FIBT, 2-(p-Methylaminophenyl)-7-(2-[18F]fluoroethoxy)imidazo-[2,1-b]benzothiazole, is a new selective PET tracer under clinical investigation to specifically image ß-amyloid depositions (Aß) in humans in-vivo that binds to Aß with excellent affinity (Kd 0.7 ± 0.2) and high selectivity over tau and α-synuclein aggregates (Ki > 1000 nM). We aimed to characterize 18F-FIBT in a series of patients with different clinical-pathophysiological phenotypes and to compare its binding characteristics to the reference compound PiB. Six patients (mild late-onset and moderate early-onset AD dementia, mild cognitive impairment due to AD, intermediate likelihood, mild behavioral variant of frontotemporal dementia, subjective memory impairment without evidence of neurodegeneration, and mild dementia due to Posterior Cortical Atrophy) underwent PET imaging with 18F-FIBT on PET/MR. With the guidance of MRI, PET images were corrected for partial volume effect, time-activity curves (TACs) of regions of interest (ROIs) were extracted, and non-displaceable binding potentials (BPnd), standardized uptake value ratios (SUVR), and distribution volume ratio (DVR) were compared. Specific binding was detected in the cases with evidence of the AD pathophysiological process visualized in images of BPnd, DVR and SUVR, consistently with patterns of different tracers in previous studies. SUVR showed the highest correlation with clinical severity. The previous preclinical characterization and the results of this case series suggest the clinical usefulness of FIBT as a selective and highly affine next-generation 18F-labeled tracer for amyloid-imaging with excellent pharmacokinetics in the diagnosis of neurodegenerative diseases. The results compare well to the gold standard PiB and hence support further investigation in larger human samples.

Correction: 18F-FIBT may expand PET for ß-amyloid imaging in neurodegenerative diseases.

The author listing has been updated to indicate that Timo Grimmer and Kuangyu Shi are equally contributing authors.

[Catatonic walks with Emil Kraepelin, Aloys Alzheimer, Henry Aloysius Cotton and others]. / Katatones Wandern mit Emil Kraepelin, Aloys Alzheimer, Henry Aloysius Cotton und anderen.

Staff outings of Emil Kraepelin's Royal Department of Psychiatry were known as "catatonic walks". A remarkable number of important German and international visitors participated in 1906, Nicolas Achucarro, Henry Cotton, Eduard Flatau, Smith Ely Jelliffe, Gaetano Perusini, Edward Scripture, Maurycy Urstein and others. Many of Kraepelin's collaborators were inspired by his ideas and driven by scientific enthusiasm which contributed to significant scientific advances, but also took them to very different ends from dental and bowel surgery to psychoanalysis and eventually evidence-based medicine; from racial hygiene and nationalism to the presidency of communist Romania.

Aging Heads of State: The Politics of Dementia and Geriatric Cognitive Disorders.

BACKGROUND: Increasing life expectancy may explain why more elderly candidates appear to be running for office. This raises general questions regarding the specific risks of old age and frailty in demanding political positions. Therefore, I tried to give important contemporary examples of elderly leaders, study the mean age of leading political figures over the last 3 decades and present historical examples of heads of state with age-associated brain diseases and cognitive deficits. I reviewed the literature on mental illness and politics and analyzed the ages of international political leaders in 1990, 2000, 2010 and 2020. SUMMARY: There are several impressive contemporary examples of elderly politicians. The mean age of political leaders has not increased significantly in most parts of the world over the last 3 decades with the exception of the Gulf States and sub-Saharan Africa. Health problems of heads of state in earlier centuries had not been primarily age associated. After 1900, dementia but also mild cognitive and mild behavioral impairment became important issues in politically critical situations, for example international peace negotiations, the rise of Nazi Germany, the breakup of communism, the Arab Spring and others. Key Messages: This paper collects anecdotal evidence of cognitive frailty in ageing politicians; it is not an in-depth analysis of political history. Observations confirm that a very long time in power may obviously increase the risk of age-associated problems; dynamic revolutionary or entrepreneurial idols may be misled to rely on their irreplaceable charisma for too long. However, caution must be exercised against ageism on one side versus silent acquiescence towards leaders with failing mental powers on the other, who may become victims of obscure parties and their decompensating personality disorders.

Correction to: Amyloid PET, FDG-PET or MRI? - the power of different imaging biomarkers to detect progression of early Alzheimer's disease.

Following publication of the original article [1], the authors ask to correct the surname of co-author Dennis Hedderich from from Heddderich to Hedderich.

BACE inhibition-dependent repair of Alzheimer's pathophysiology.

Amyloid-ß (Aß) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aß is the ß-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aß levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aß surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aß, mechanistically linking Aß pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.

The overnight reduction of amyloid ß 1-42 plasma levels is diminished by the extent of sleep fragmentation, sAPP-ß, and APOE ε4 in psychiatrists on call.

INTRODUCTION: In mice there might be an association between sleep deprivation and amyloid ß plasma levels. Hence, we examined whether amyloid plasma levels are associated with sleep duration or fragmentation in 17 psychiatrists on-call. METHODS: Amyloid ß (Aß)42, Aß40, and soluble amyloid precursor protein ß (sAPP-ß) plasma concentrations were measured at the beginning and end of 90 on-call nights, and analyzed using generalized linear models. RESULTS: In on-call nights, a 10.7% reduction of Aß42 was revealed overnight. Every single short sleep interruption diminished this reduction by 5.4%, as well as every pg/mL of sAPP-ß by 1.2%, each copy of APOE ε4 by 10.6%, and each year of professional experience by 3.0%. DISCUSSION: The extent of sleep fragmentation diminishes the physiological overnight reduction of Aß42 but not Aß40 plasma levels in the same direction as the enzyme for Aß42 production, the genetic risk factor for Alzheimer's disease (AD), and on-call experience. Might on-call duty and sleep fragmentation in general alter the risk for AD?

Amyloid PET, FDG-PET or MRI? - the power of different imaging biomarkers to detect progression of early Alzheimer's disease.

BACKGROUND: As investigations of disease modifying drugs aim to slow down progression of Alzheimer' disease (AD) biomarkers to reliably track disease progression gain more importance. This is especially important as clinical symptoms, including psychometric measures, are only modestly associated with the underlying disease pathology, in particular at the pre-dementia stages. The decision which biomarkers to choose in clinical trials is crucial and depends on effect size. However, longitudinal studies of multiple biomarkers in parallel that allow direct comparison on effect size are scarce. METHODS: We calculated effect size and minimal sample size for three common imaging biomarkers of AD, namely amyloid deposition measured with PiB-PET, neuronal dysfunction measured with FDG-PET and cortical thickness measured with MRI in a prospective 24-month follow-up study in a monocentric cohort of early AD. RESULTS: Post hoc power calculation revealed large effect sizes of Cohen's d for PiB-PET and cortical thickness and a small effect size for FDG-PET (1.315, 0.914, and 0.341, respectively). Accordingly, sample sizes for PiB-PET and cortical thickness required significantly smaller sample sizes than FDG-PET to reliably detect statistically significant changes after 24 months in early AD (n = 7, n = 12, and n = 70, respectively). CONCLUSION: Amyloid imaging with PET and measuring cortical thickness with MRI are suitable biomarkers to detect disease progression in early AD within a small sample.

Associations of Neprilysin Activity in CSF with Biomarkers for Alzheimer's Disease.

BACKGROUND: Neprilysin (NEP) cleaves amyloid-ß 1-42 (Aß42) in the brain. Hence, we aimed to elucidate the effect of NEP on Aß42 in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [11C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. METHODS: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer's disease patients. RESULTS: CSF-NEP was significantly inversely associated with CSF-Aß42 and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. CONCLUSIONS: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer's pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

Epilepsy as a Network Disorder (2): What can we learn from other network disorders such as dementia and schizophrenia, and what are the implications for translational research?

There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitating side effects. Interestingly, some of the 'complexities' of one disorder are found in another, and the similarities are often network defects. It seems likely that more discussions of these commonalities could advance our understanding and, therefore, have clinical implications or translational impact. With this in mind, the Fourth International Halifax Epilepsy Conference and Retreat was held as described in the prior paper, and this companion paper focuses on the second half of the meeting. Leaders in various subspecialties of epilepsy research were asked to address aging and dementia or psychosis in people with epilepsy (PWE). Commonalities between autism, depression, aging and dementia, psychosis, and epilepsy were the focus of the presentations and discussion. In the last session, additional experts commented on new conceptualization of translational epilepsy research efforts. Here, the presentations are reviewed, and salient points are highlighted.

IssuEs in Palliative care for people in advanced and terminal stages of Young-onset and Late-Onset dementia in GErmany (EPYLOGE): the study protocol.

BACKGROUND: Scientific research on palliative care in dementia is still underdeveloped. In particular, there are no research studies at all on palliative care issues in young onset dementia (YOD), although significant differences compared to late onset dementia (LOD) are expected. Most studies have focused on persons with dementia in long term care (LTC) facilities but have neglected persons that are cared for at home. We hypothesize that unmet care needs exist in advanced and terminal stages of YOD and LOD and that they differ between YOD and LOD. METHODS/DESIGN: The EPYLOGE-study (IssuEs in Palliative care for people in advanced and terminal stages of Young-onset and Late-Onset dementia in GErmany) aims to prospectively assess and survey 200 persons with YOD and LOD in advanced stages who are cared for in LTC facilities and at home. Furthermore, EPYLOGE aims to investigate the circumstances of death of 100 persons with YOD and LOD. This includes 1) describing symptoms and management, health care utilization, palliative care provision, quality of life and death, elements of advance care planning, family caregivers' needs and satisfaction; 2) comparing YOD and LOD regarding these factors; 3) developing expert-consensus recommendations derived from the study results for the improvement and implementation of strategies and interventions for palliative care provision; 4) and communicating the recommendations nationally and internationally in order to improve and adapt guidelines, to change current practice and to give a basis and perspectives for future research projects. The results will also be communicated to patients and their families in order to counsel and support them in their decision making processes and their dialogue with professional caregivers and physicians. DISCUSSION: EPYLOGE is the first study in Germany that assesses palliative care and end-of-life issues in dementia. Furthermore, it is the first study internationally that focuses on the specific palliative care situation of persons with YOD and their families. EPYLOGE serves as a basis for the improvement of palliative care in dementia. TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov ( NCT03364179 ; Registered: 6. December 2017.

[Impaired recognition of environmental sounds in patients with dementia : I can hear but I do not understand]. / Störung des Erkennens von Umweltgeräuschen bei Demenz : Ich höre aber ich verstehe nicht.

BACKGROUND: Impairment of central auditory processing is a well-known symptom of neurodegenerative dementia; however, whilst numerous studies have examined verbal processing impairment, to date few have attempted to describe impairments of non-verbal, environmental sound recognition in patients with dementia. As these impairments may have direct implications on patient support and care, such studies are urgently necessary. AIM OF THE STUDY: The aim of the study was to determine whether the recognition of meaningful environmental sounds is impaired in patients with mild or early stage neurodegenerative dementia. PATIENTS AND METHODS: We developed a test of non-verbal sound recognition consisting of 16 sound sequences from the familiar and unfamiliar environments. We included 18 patients with mild cognitive impairment and mild dementia caused by Alzheimer's disease and frontotemporal dementia, as well as 20 cognitively healthy controls. RESULTS: Patients and controls were given the test of recognizing 16 meaningful sounds from the familiar and unfamiliar environments. Patients with dementia performed significantly worse in comparison to cognitively healthy controls. Whilst healthy controls correctly recognized on average 12.1 ± 2.2 out of 16 sounds, cognitively impaired patients recognized 9.2 ± 2.5. Correlation analysis showed that the mini mental state examination (MMSE) scores were positively correlated with the number of correctly recognized sounds (MMSE: r = 0.556, p = 0.017). DISCUSSION: The fact that even in mild stages of Alzheimer's disease or frontotemporal dementia patients either do not recognize or misinterpret environmental sounds must be taken into consideration not only in everyday life but in particular when patients need to leave their familiar living environment, whether temporarily (e. g. hospitalization) or permanently (e. g. nursing home admission).

Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode.

BACKGROUND: In patients with schizophrenia in a psychotic episode, intra-striatal intrinsic connectivity is increased in the putamen but not ventral striatum. Furthermore, multimodal changes have been observed in the anterior insula that interact extensively with the putamen. AIMS: We hypothesised that during psychosis, putamen extra-striatal functional connectivity is altered with both the anterior insula and areas normally connected with the ventral striatum (i.e. altered functional connectivity distinctiveness of putamen and ventral striatum). METHOD: We acquired resting-state functional magnetic resonance images from 21 patients with schizophrenia in a psychotic episode and 42 controls. RESULTS: Patients had decreased functional connectivity: the putamen with right anterior insula and dorsal prefrontal cortex, the ventral striatum with left anterior insula. Decreased functional connectivity between putamen and right anterior insula was specifically associated with patients' hallucinations. Functional connectivity distinctiveness was impaired only for the putamen. CONCLUSIONS: Results indicate aberrant extra-striatal connectivity during psychosis and a relationship between reduced putamen-right anterior insula connectivity and hallucinations. Data suggest that altered intrinsic connectivity links striatal and insular pathophysiology in psychosis.

Current issues and future research priorities for health economic modelling across the full continuum of Alzheimer's disease.

Available data and models for the health-economic evaluation of treatment in Alzheimer's disease (AD) have limitations causing uncertainty to decision makers. Forthcoming treatment strategies in preclinical or early AD warrant an update on the challenges associated with their economic evaluation. The perspectives of the co-authors were complemented with a targeted review of literature discussing methodological issues and data gaps in AD health-economic modelling. The methods and data available to translate treatment efficacy in early disease into long-term outcomes of relevance to policy makers and payers are limited. Current long-term large-scale data accurately representing the continuous, multifaceted, and heterogeneous disease process are missing. The potential effect of disease-modifying treatment on key long-term outcomes such as institutionalization and death is uncertain but may have great effect on cost-effectiveness. Future research should give priority to collaborative efforts to access better data on the natural progression of AD and its association with key long-term outcomes.